Early in vertebrate embryonic development, cell-cell signaling plays important roles. We are interested in the mechanistic understanding of Wnt and hedgehog signaling pathways in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt and hedgehog family members determines where and when the late structures, ie, skeletal elements will form. Skeletal morphogeneis in the limb occurs through endochondral bone formation in which chondrocytes (they form the cartilage) and osteoblasts (they secrete bone matrix) are first differentiated from mesenchymal condensations. This is followed by sequential proliferation and maturation of both chondrocytes and osteoblasts, which are tightly regulated and coordinated to ensure proper morphogenesis of the skeletal system. The underlying molecular mechanism has just begun to be elucidated in recent years. Through analyzing mutant mice in which Wnt and hedgehog signaling components are either inactivated or ectopically expressed, we have found that Wnt5a is required for the transition from proliferative chondrocytes to prehypertrophic chondrocytes in a pathway in parallel with Indian Hedgehog (Ihh) and parathyroid hormone related peptide.(PTHrP). By a combined approaches of mouse genetics and in vitro cell and organ cultures, we are studying the mechanism by which Wnt5a transduce its signal and cross-talk with other signaling pathways to regulate chondrocyte differentiation.